Agents that stimulate therapeutic angiogenesis and techniques and devices that enable their delivery

ABSTRACT

A method including positioning a catheter at a location in a blood vessel; imaging a thickness of a portion of a wall of the blood vessel at the location; identifying a treatment site; advancing a needle a distance into the wall of the blood vessel to the treatment site; and introducing a treatment agent through the needle to the treatment site. A composition including an inflammation-inducing agent and a carrier in the form of microspheres having a particle size suitable for transvascular delivery. A composition including a therapeutic angiogenesis promoter in a carrier and an opsonin-inhibitor coupled to the carrier. An apparatus for delivery of a therapeutic angiogenesis promoter.

BACKGROUND

[0001] 1. Field

[0002] This invention relates to resolving ischemia by inducingformation of blood vessels through therapeutic angiogenesis.

[0003] 2. Relevant Art

[0004] A major component of morbidity and mortality attributable tocardiovascular disease occurs as a consequence of the partial orcomplete blockage of vessels carrying blood in the coronary and/orperipheral vasculature. When such vessels are partially occluded, lackof blood flow causes ischemia to the muscle tissues supplied by suchvessel, consequently inhibiting muscle contraction and proper function.Total occlusion of blood flow causes necrosis of the muscle tissue.

[0005] Blood vessel occlusions are commonly treated by mechanicallyenhancing blood flow in the affected vessels. Such mechanicalenhancements are often provided by employing surgical techniques thatattach natural or synthetic conduits proximal and distal to the areas ofocclusion, thereby providing bypass grafts, or revascularization byvarious means to physically enlarge the vascular lumen at the site ofocclusion. These revascularization procedures involve such devices asballoons, endovascular knives (atherectomy), and endovascular drills.The surgical approach is accompanied by significant morbidity and evenmortality, while the angioplasty-type processes are complicated byrecurrent stenoses in many cases.

[0006] In some individuals, blood vessel occlusion is partiallycompensated by natural processes, in which new vessels are formed(termed “angiogenesis”) and small vessels are enlarged (termed“arteriogenesis”) to replace the function of the impaired vessels. Thesenew conduits may facilitate restoration of blood flow to the deprivedtissue, thereby constituting “natural bypasses” around the occludedvessels. However, some individuals are unable to generate sufficientcollateral vessels to adequately compensate for the diminished bloodflow caused by cardiovascular disease. Accordingly, it would bedesirable to provide a method and apparatus for delivering agents tohelp stimulate the natural process of therapeutic angiogenesis tocompensate for blood loss due to an occlusion in a coronary andperipheral arteries in order to treat ischemia.

SUMMARY

[0007] A method is disclosed. In one embodiment the method includespositioning a delivery device such as a catheter at a location in ablood vessel and advancing the delivery device a distance into a wall ofthe blood vessel to a treatment site. A treatment agent is thenintroduced through the delivery device to the treatment site. The methodalso includes identifying a treatment site based on imaging a thicknessof a portion of the wall of the blood vessel. In the example ofintroducing a treatment agent that would stimulate a therapeuticangiogenesis response, the method describes a technique for accuratelydelivering a treatment agent into the wall of the blood vessel or beyondthe wall of the blood vessel as the particular situation may dictate.The method utilizes imaging of a thickness of the wall of a blood vesselto accurately place the treatment agent. Suitable imaging techniquesinclude, but are not limited to, ultrasonic imaging, optical imaging,and magnetic resonance imaging.

[0008] In another embodiment, a method includes introducing a treatmentagent in a sustained release composition or carrier. Treatment agentsthat can sustain their effectiveness for a period of up to one to tenweeks, preferably two to eight weeks, offer maximum benefit for thestimulation of therapeutic angiogenesis. Methods of inducing coronary orperipheral therapeutic angiogenesis by local delivery of sustainedrelease treatment agents using percutaneous devices are described. Suchdevices may be intraventricular (coronary) or intravascular (coronaryand peripheral).

[0009] In another embodiment, a method includes placing a treatmentagent in or around a blood vessel or other tissue that stimulatestherapeutic angiogenesis by inducing an inflammation response in tissue.

[0010] In still another embodiment, a sustained-release compositioncomprising a treatment agent in a form suitable for transvasculardelivery is described. Also, a composition comprising a carrierincluding a treatment agent and an opsonin-inhibitor coupled to thecarrier.

[0011] In a further embodiment, an apparatus is described that allowsthe accurate introduction of a treatment agent in or around a bloodvessel. The apparatus includes, for example, a catheter body capable oftraversing a blood vessel and a dilatable balloon assembly coupled tothe catheter body comprising a balloon having a proximal wall. A needlebody is disposed within the catheter body and comprises a lumen havingdimensions suitable for a needle to be advanced there through. Theneedle body includes an end coupled to the proximal wall of the balloon.The apparatus also includes an imaging body disposed within the catheterbody and comprising a lumen having a dimension suitable for a portion ofan imaging device to be advanced there through. The apparatus furtherincludes a portion of an imaging device disposed within the imaging bodyadapted to generate imaging signals of the blood vessel, includingimaging signals of a thickness of the wall of a blood vessel. Anapparatus such as described is suitable for accurately introducing atreatment agent at a desired treatment site in or around a blood vessel.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012]FIG. 1 schematically illustrates a perspective and cross-sectionview of a blood vessel:

[0013]FIG. 2 schematically illustrates a planar cross-sectional view ofcomponents of a coronary artery network;

[0014]FIG. 3 is a simplified cross-sectional view of an embodiment of asubstance delivery apparatus in the form of a catheter assembly having aballoon and a therapeutic substance delivery assembly;

[0015]FIG. 4 schematically illustrates a planar cross-section of thesubstance delivery apparatus of FIG. 3 through line A-A′;

[0016]FIG. 5 schematically illustrates a planar cross-section of thesubstance delivery apparatus of FIG. 3 through line B-B′;

[0017]FIG. 6 schematically illustrates a cross-sectional view of thedistal section of the substance delivery apparatus of FIG. 3 with theballoon in an undeployed configuration;

[0018]FIG. 7 schematically illustrates a cross-sectional view of thedistal section of the substance delivery apparatus of FIG. 3 with theballoon in a deployed configuration;

[0019]FIG. 8 schematically illustrates an optical imaging system for usein a substance delivery apparatus such as a catheter assembly;

[0020]FIG. 9 schematically illustrates a cross-sectional side view ofcomponents of an alternative catheter assembly including an opticalimaging system.

[0021]FIG. 10 schematically illustrates the left coronary artery networkhaving a catheter assembly introduced therein; and

[0022]FIG. 11 presents a block diagram for introducing a treatmentagent.

[0023] The features of the described embodiments are specifically setforth in the appended claims. However, the embodiments are bestunderstood by referring to the following description and accompanyingdrawings, in which similar parts are identified by like referencenumerals.

DETAILED DESCRIPTION

[0024] In connection with the description of the various embodiments,the following definitions are utilized:

[0025] “Therapeutic angiogenesis” refers to the processes of causing orinducing angiogenesis and arteriogenesis.

[0026] “Angiogenesis” is the promotion or causation of the formation ofnew blood vessels in the ischemic region.

[0027] “Arteriogenesis” is the enlargement of pre-existing collateralvessels. The collateral vessels allow blood to flow from a well-perfusedregion of the vessel into the ischemic region.

[0028] “Ischemia” is a condition where oxygen demand of the tissue isnot met due to localized reduction in blood flow caused by narrowing orocclusion of one or more vessels. Narrowing of arteries such as coronaryarteries or their branches, is most often caused by thrombosis or viadeposits of fat, connective tissue, calcification of the walls, orrestenosis due to abnormal migration and proliferation of smooth musclecells.

[0029] “Occlusion” is the total or partial obstruction of blood flowthrough a vessel.

[0030] “Treatment agent” includes agents directed to specific cellularbinding sites (e.g., receptor binding treatment agents) and agents thatinduce inflammation.

[0031] “Specific binding treatment agent” or “receptor binding treatmentagent” includes a protein or small molecule that will induce and/ormodulate a therapeutic angiogenic response through interaction with aspecific binding site (e.g., a binding within a cell or on a cellsurface). Representative treatment agents include, but are not limitedto, vascular endothelial growth factor (VEGF) in any of its multipleisoforms, fibroblast growth factors, monocyte chemoattractant protein 1(MCP-1), transforming growth factor beta (TGF-beta) in any of itsmultiple isoforms, transforming growth factor alpha (TGF-alpha), lipidfactors, hypoxia-inducible factor 1-alpha (HIF-1-alpha), PR39, DEL 1,nicotine, insulin-like growth factors, placental growth factor (PIGF),hepatocyte growth factor (HGF), estrogen, follistatin, proliferin,prostaglandin E1, prostaglandin E2, cytokines, tumor necrosis factor(TNF-alpha), erythropoietin, granulocyte colony-stimulating factor(G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF),angiogenin, hormones, and genes that encode such substances.

[0032] “Non-specific treatment agent” includes, as described in moredetail herein, various agents that induce inflammation.

[0033] “Carrier” includes a matrix that contains one or more treatmentagents. A suitable carrier may take the form of a nanoparticle (e.g.,nanosphere) or microparticle (e.g., microsphere) as the situation maydictate.

[0034] Referring to FIG. 1, a non-diseased artery is illustrated as arepresentative blood vessel. Artery 100 includes an arterial wall havinga number of layers. Innermost layer 110 is generally referred to as theintimal layer that includes the endothelium, the subendothelial layer,and the internal elastic lamina. Medial layer 120 is concentricallyoutward from intimal layer 110 and bounded by external elastic laminaand adventitial layer 130 is the outermost layer. There is no externalelastic lamina in a vein. Medial layer 120 (in either an artery or vein)primarily consists of smooth muscle fibers and collagen. Beyond mediallayer 120 and adventitial layer 130 lies the extravascular tissueincluding, adjacent adventitial layer 120 (and possibly including aportion of adventitial layer 120), area 140 referred to asperi-adventitial site (space) or area. Areas radially outward from aperi-adventitial space include connective tissue such as adipose tissuethat is most likely located, in terms of areas around the heart, towardthe epicardial surface of the heart and myocardial tissue composed ofmuscle fibers.

[0035]FIG. 2 illustrates components of a coronary artery network. Inthis simplified example, vasculature 150 includes left anteriordescending artery (LAD) 160, left circumflex artery (LCX) 170 and rightcoronary artery (RCA) 180. Sites 190A, 190B, and 190C are preferably inthe peri-adventitial space or radially outward from the peri-adventitialspace (e.g., in adipose or myocardial tissue). Occlusion 185 is shown inLCX 170. Occlusion 185 limits the amount of oxygenated blood flowthrough LCX 170 to the myocardium that it supplied, resulting inischemia of this tissue.

[0036] To improve the function of the artery network, it is generallydesired to either remove occlusion 185 (for example through anangioplasty procedure), bypass occlusion 185 or induce therapeuticangiogenesis to makeup for the constriction and provide blood flow tothe ischemic region (e.g., downstream of occlusion 185). FIG. 2 showstherapeutic angiogenesis induced at sites 190A (associated with LCX170); 190B (associated with LAD 160); and 190C (associated with RCA180). By inducing therapeutic angiogenesis at sites 190A, 190B, and190C, permanent revascularization of the network is accomplished, thuscompensating for reduced flow through LCX 170. The following paragraphsdescribe compositions, techniques and an apparatus suitable for inducingtherapeutic angiogenesis.

A. Specific Binding Treatment Agents

[0037] In one embodiment, therapeutic angiogenesis is induced andmodulated by locally delivering a treatment agent in a sustained-releasecarrier. The sustained-release carrier comprising a treatment agent maybe strategically placed, for example, along an occlusion to produce anangiogenic concentration gradient to encourage the specific directionalgrowth or expansion of collateral vessels. For example, in reference toFIG. 2, treatment agents placed at zone 190A, above (as viewed) occludedvessel LCX 170 are selected such that, while up-stream, a therapeuticangiogenic or arteriogenic response will encourage growth of collateralsaround occlusion 185 meeting up with LCX 170 down-stream of theocclusion. Similarly, a treatment agent strategically placed at alocation in a region near to left coronary artery 160 (e.g., region190B) will encourage bridging of collateral vessels, in this case,between left coronary artery 160 and LCX 170. Similar encouragement andbridging may be obtained by strategically placing a treatment agent at aregion of RCA 180 (such as region 190C). While the application oftherapeutic angiogenesis to alleviating ischemia resulting from a flowlimiting obstruction in the LCX is described, those familiar with theart will appreciate that the method described is applicable to thetreatment of flow limiting obstructions in other coronary vessels and inthe peripheral vasculature.

[0038] Suitable treatment agents include specific binding or receptorbinding treatment agents. Suitable sustained-release carriersencapsulating the specific binding agents may take the form of polymernanoparticles or microparticles, typically in the form of nanospheres ormicrospheres, having an average particle size less than 100 microns (am)and preferably less than about 10 μm to, in one aspect, enable deliverythrough a catheter equipped with an injection needle. Sustained releaseof treatment agents for a period of up to one to ten weeks, preferablyup to two to eight weeks is believed to offer maximum benefit for thestimulation of therapeutic angiogenesis. In another embodiment, thesustained release of treatment agents over a period of one day or longeris preferred. The loading of the receptor binding treatment agent in thesustained release carrier is in the range of about 0.5 percent to about30 percent weight by volume (w/v), and the total dose of the receptorbinding treatment agent delivered to the treatment location is in therange of about 1 microgram (μg) to about 1 gram (g).

[0039] Sustained release microparticle formulations with differentrelease rates may be delivered in combination to achieve multi-modalrelease profiles over a period of time.

B. Non-Specific Treatment Agents

[0040] As stated above, specific binding or receptor binding treatmentagents can induce therapeutic angiogenesis. One embodiment of anothersuitable treatment agent that will induce and/or modulate a therapeuticangiogenic response is an inflammation-inducing agent. Studies haveshown that tissue, including blood vessels, respond to injury induced byimplanting foreign materials in three broad phases. The first phase ischaracterized by minimal inflammatory reaction, with the presence of afew lymphocytes, plasma cells, monocytes, and polymorphonuclearleukocytes. The response to injury in this first phase is determinedprimarily by the extent of injury caused, for example, by a needle of aneedle catheter contacting a blood vessel and the volume of therapeuticsubstance (e.g., treatment agent) injected to the site of interest. Thesecond response to injury phase is characterized by a predominance ofmonocytes and macrophages. In the case of biodegradable implants, theduration of this second phase is determined by the rate ofbiodegradation of the carrier. During this phase, monocytesdifferentiate into macrophages at the site of injury and the macrophagesthemselves fuse into foreign body “giant” cells. Fibroblast infiltrationand neoangiogenesis are also observed at this stage. For biodegradableimplants, there is a third response to injury phase, characterized bythe breakdown of the biodegradable material. In this phase, macrophagespredominate at the site of implantation. The extent of inflammation andthe concentration of monocyte/macrophages at the implantation sitereaches a peak at this third phase. Monocyte accumulation and activationis thought to be a potent means of inducing therapeutic angiogensis

[0041] In one embodiment, ischemic regions supplied by a blood vesselsuch as ischemic region caused by a lesion in the LCX 170 in FIG. 2 maybe treated by implantation of an inflammation-inducing agent (a“non-specific” agent) optionally combined with or contained in(encapsulated) a sustained-release carrier. The implantation may beaccomplished non-invasively through, for example, catheter-basedtechnologies, minimally invasively, or in conjunction with surgicalprocedures. The extent and duration of inflammation is dependent on thenon-specific agent being implanted. A combination of agents may beimplanted to modulate the extent of inflammation over a period of time,which is typically on the order of about two weeks to about eight weeks.

[0042] Suitable inflammation-inducing agents include, but are notlimited to, (1) bioresorbable inorganic compounds such as sol gelparticles and calcium phosphate glass comprising iron; (2) fibrin,gelatin, low molecular weight hyaluronic acid, and chitin; (3) bacterialpolysaccharides; (4) metals; and (5) certain other polymers (whichthemselves may function as both treatment agent and carrier, including asustained-release carrier) including bioresorbable polymers such aspolycaprolactone (PCL), polyhydroxybutyrate-valerate (PHBV),poly(oxy)ethylene (POE), and non-bioresorbable polymers such aspolyurethanes and silicones. The inflammation-inducing treatment agentmay be combined as a composition with one or more other specific bindingor receptor binding treatment agents that are believed to inducetherapeutic angiogenesis such as growth factors.

[0043] Representative examples of inflammation-inducing treatment agentsthat may be combined, in one embodiment, with a sustained releasecarrier include the following.

[0044] Silica sol gel particles, such as manufactured by Bioxid LTD OYof Turku, Finland, are bioresorbable inorganic compounds that can bepro-inflammatory on their own and also serve as a drug eluting reservoirfor other pro-inflammatory agents (e.g., lipopolysaccharides (LPS),chitin, etc.). Calcium-phosphate glass containing iron will degrade in ahumid environment as a function of the iron composition, resulting in anabsorbable glass. One example of absorbable glass is made by MOSCI, Inc.of Rolla, Mo. The absorbable glass may induce controlled inflammation bythe physical dimension of the degradation product. A combination of PLGAcoated (with or without activation) or partially coated absorbable glassmay be employed to modulate the degradation rate of different species.

[0045] Chitin is a polysaccharide derived principally from crab shells,and shows a pro-inflammatory reaction. Micronized chitin can beincorporated into microspheres or disbursed into a polymer system suchas described above to enhance the inflammatory action of treatment agentof microspheres or precipitated polymers. The micronized chitin can alsobe disbursed in a gel that may then be extruded via a needle catheter toa desired treatment location (within the vascular or myocardium).Gelatin (a partially degraded form of collagen) and fibrin may beutilized in a similar manner.

[0046] The outer membranes of gram-negative bacteria containinglipopolysaccharides (LPS) can be pro-inflammatory. Isolation of LPS andincorporation into degradeable microspheres can enhance the inflammatoryreaction of the microspheres and provide a more potent angiogenicaction.

[0047] The cell walls of blood vessels are typically rich in glycocalyxand other specific antigens. Systemic immune response may be upregulatedby administration of vaccines or denatured proteins such as Ab, Fb, etc.In another embodiment, the localized introduction (e.g., through acatheter) of vaccines or certain denatured proteins may be used incombination with, for example, inflammatory-inducing treatment agents topotentiate the controlled inflammatory effect

[0048] Particles of metal such as gold (Au) and titanium (Ti) are knownto induce inflammation and activate monocytes. These particles may beinjected as a suspension at a local site of interest via, for example, aneedle catheter. To amplify an effect, such thermally conductiveparticles can be heated with, for example, using a 900 to 1200 nanometer(nm) range remote source of radio frequency energy to further causecontrolled damage to the tissue resulting in inflammation and promotingtherapeutic angiogenesis; 10 to 100 nanometer (nm) spherical particlesare shown to have this remote activatible heating effect.

C. Methods of Forming Sustained Release Particles

[0049] In the previous paragraphs, both specific binding treatmentagents and non-specific binding treatment agents have been described inconjunction with promoting therapeutic angiogenesis. Such promotion isencouraged, in one embodiment, by delivering the treatment agent in orwith a sustained-release carrier. Suitable materials forsustained-release carriers include, but are not limited to,encapsulation polymers such as poly (L-lactide), poly (D,L-lactide),poly (glycolide), poly (lactide-co-glycolide), polycaprolactone,polyanhydride, polydiaxanone, polyorthoester, polyamino acids, or poly(trimethylene carbonate), and combinations thereof. To form asustained-release carrier composition of, for example, microparticles ornanoparticles (e.g., microspheres or nanospheres) comprising one or moretreatment agents including a non-specific treatment agent and/or aspecific binding agent, the following techniques may be used.

[0050] 1. Solvent Evaporation

[0051] In this method, the polymer is dissolved in a volatile organicsolvent such as methylene chloride. The treatment agent is then added tothe polymer solution either as an aqueous solution containing anemulsifying agent such as polyvinyl alcohol (PVA), or as a soliddispersion, and stirred, homogenized or sonicated to create a primaryemulsion of protein in the polymer phase. This emulsion is stirred withan aqueous solution containing an emulsifying agent such as PVA tocreate a secondary emulsion of treatment agent containing polymer in theaqueous phase. This emulsion is stirred in excess water, optionallyunder vacuum to remove the organic solvent and harden the particles. Thehardened particles are collected by filtration or centrifugation andlyophillized. A desired particle size (e.g., microparticle ornanoparticle) may be selected by varying the preparation conditions(e.g., viscosity of the primary emulsion, concentration of the treatmentagent, mixing (shear) rate, etc.). The particles tend to adopt aspherical shape in response to minimizing surface tension effects.

[0052] 2. Coacervation:

[0053] In this method, a primary emulsion of treatment agent in anaqueous phase is formed as in the solvent evaporation method. Thisemulsion is then stirred with a non-solvent for the polymer, such assilicone oil to extract the organic solvent and form embryonic particlesof polymer with trapped treatment agent. The non-solvent is then removedby the addition of a volatile second non-solvent such as heptane, andthe particles hardened. The hardened particles are collected byfiltration or centrifugation and lyophillized. Again, the particle sizemay be selected as described above with reference to solventevaporation.

[0054] 3. Spray Drying:

[0055] In this method, the treatment agent, formulated as lyophilizedpowder is suspended in a polymer phase consisting of polymer dissolvedin a volatile organic solvent such as methylene chloride. The suspensionis then spray dried to produce polymer particles with entrappedtreatment agent. The particle size may be selected as described abovewith reference to solvent evaporation.

[0056] 4. Cryogenic process:

[0057] In this method, the treatment agent, formulated as lyophillizedpowder is suspended in a polymer phase consisting of polymer dissolvedin a volatile organic solvent such as methylene chloride. The suspensionis sprayed into a container containing frozen ethanol overlaid withliquid nitrogen. The system is then warmed to −70° C. to liquify theethanol and extract the organic solvent from the treatment agentparticles. The hardened microspheres are collected by filtration orcentrifugation and lyophillized.

[0058] 5. In situ Process:

[0059] Sustained release carriers (e.g., microparticles and/ornanoparticles) may be formed before introduction (e.g., injection) intothe blood vessel as described above, or they may be formed in situ. Oneway to form such particles in situ is by co-desolving a treatment agentand a matrix forming polymer in a water miscible solvent such asdimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), ethanol orglycofural and injecting the solution at the site of treatment with, forexample, a catheter to precipitate out polymer particles. Severalpolymer solutions, each consisting of a polymer formulation with adifferent degradation rate can be injected in sequence to precipitateout a mixed population of polymer particles, in order to obtain amulti-modal release profile.

[0060] 6. Example of Loading and Dose for Inducing/ModulatingTherapeutic Angiogenesis

[0061] As noted above, one example of the preparation of nanoparticles(e.g., nanospheres) or microparticles (e.g., microspheres) suitable foruse in therapeutic angiogenesis is in the form of a solution.Nanoparticles or microparticles may be loaded with specific ornon-specific agents in the range of 0.5-30 percent w/v. In the case ofinflammatory agents, loading may be as high as 100 percent w/v. Asuitable dose may be calculated as follows:

DOSE=number of injections×% suspension of nano- and/ormicroparticles[(weight of nano- and/or microparticles)/volume ofsolution]×volume of solution×% loading[weight of agent/(weight of nano-and/or microparticles)].

[0062] Using an inflammatory treatment agent such as gold particles asan example, loading may be 100 percent. In 0.2 ml solution five percentw/v of particles provides for maximal dose of 10 micrograms of materialper injection. The number of injections is determined by an operator.The total dose is in the range of 1 microgram to 1 gram. It is to beappreciated that the optimal dose may be determined in a relevant animalmodel of ischemia by delivering the nano- and/or microparticlesuspension through a needle catheter or simply by injecting duringopen-heart procedure and generating a dose-response curve.

D. Compositions Having a Particle Size of 10 Microns or Less

[0063] Treatment agents, including treatment agents combined with acarrier (e.g., a sustained release carrier), having a particle sizegreater than approximately 10 microns have the potential, whenintroduced into the arterial vascular system, of being trapped in thecapillary bed. Trapping large numbers of microparticles in the capillarybed could result in ischemia. Treatment agent compositions havingparticle diameters less than about 10 microns, however, are rapidlyphagocytosed, resulting in reduced availability of the treatment agentat target sites, where, for example, sustained-released of the treatmentagent may be desired in a certain therapeutic concentration range.

[0064] Regarding phagocytosis, when a foreign material is implanted intoa host tissue, the first event to occur at the tissue-material interfaceis the adsorption of plasma proteins from blood onto the surface of theforeign material. Opsonins are plasma proteins, such as complement andimmunoglobulin, that adhere to foreign materials such as nanoparticlesand facilitate their phagocytosis through the recognition of theadsorbed opsonins by macrophages of the reticulo-endothelial system.Microspheres larger than about 10 microns are also opsonized, but aregenerally considered too large to be phagocytosed.

[0065] In one embodiment, the treatment agent compositions suitable fortherapeutic angiogenesis are rendered resistant to phagocytosis byinhibiting opsonin protein adsorption to the composition particles. Inthis regard, treatment agent compositions including sustained releasecarriers comprise particles having an average diameter of up to about 10microns are contemplated.

[0066] One method of inhibiting opsonization and subsequent rapidphagocytosis of treatment agents is to form a composition comprising atreatment agent disposed within a carrier (e.g., a sustained releasecarrier) and to coat the carrier with an opsonin inhibitor. One suitableopsonin-inhibitor includes polyethylene glycol (PEG) which creates abrush-like steric barrier to opsonization. PEG may alternatively beblended into the polymer constituting the carrier, or incorporated intothe molecular architecture of the polymer constituting the carrier, as acopolymer, to render the carrier resistant to phagocytosis. Examples ofpreparing the opsonin-inhibited microspheres include the following.

[0067] For the encapsulation polymers, a blend of a polyalkylene glycolsuch as polyethylene glycol (PEG), polypropylene 1,2-glycol orpolypropylene 1,3-glycol is co-dissolved with an encapsulating polymerin a common organic solvent during the carrier forming process. Thepercentage of PEG in the PEG/encapsulating polymer blend is between fivepercent and 60 percent by weight. Other hydrophilic polymers such aspolyvinyl pyrolidone, polyvinyl alchohol, orpolyoxyethylene-polyoxypropylene copolymers can be used in place ofpolyalkylene glycols, although polyalkylene glycols and morespecifically, polyethylene glycol is generally preferred.

[0068] Alternatively, a diblock or triblock copolymer of anencapsulating polymer such as poly (L-lactide), poly (D,L-lactide), orpoly (lactide-co-glycolide) with a polyalkylene glycol may be prepared.Diblocks can be prepared by: (i) reacting the encapsulating polymer witha monomethoxy polyakylene glycol such as PEG with one protected hydroxylgroup and one group capable of reacting with the encapsulating polymer,(ii) by polymerizing the encapsulating polymer on to the monomethoxypolyalkylene glycol such as PEG with one protected group and one groupcapable of reacting with the encapsulating polymer; or (iii) by reactingthe encapsulating polymer with a polyalkylene glycol such as PEG withamino functional termination. Triblocks can be prepared as describedabove using branched polyalkylene glycols with protection of groups thatare not to react. Opsonization resistant carriers(microparticles/nanoparticles) can also be prepared using the techniquesdescribed above to form sustained-release carriers(microparticles/nanoparticles) with these copolymers.

[0069] A second way to inhibit opsonization is the biomimetic approach.For example, the external region of cell membrane, known as the“glycocalyx”, is dominated by glycoslylated molecules which preventnon-specific adhesion of other molecules and cells. Surfactant polymersconsisting of a flexible poly (vinyl amine) backbone randomly-dextranand alkanoyl (hexanoyl or lauroyl) side chains which constrain thepolymer backbone to lie parallel to the substrate. Hydrated dextran sidechains protrude into the aqueous phase, creating a glycocalyx-likemonolayer coating which suppresses plasma protein deposition on theforeign body surface. To mimic glycocalyx, glycocalyx-like molecules canbe coated on the carriers (e.g., nanoparticles or microparticles) orblended into a polymer constituting the carrier to render the treatmentagent resistant to phagocytosis. An alternate biomimetic approach is tocoat the carrier with, or blend in phosphorylcholine, a syntheticmimetic of phosphatidylcholine, into the polymer constituting thecarrier.

[0070] For catheter delivery, a carrier comprising a treatment agent(e.g., the composition in the form of a nanoparticle or microparticle)may be suspended in a fluid for delivery through the needle, at aconcentration of about one percent to about 20 percent weight by volume.In one embodiment, the loading of the treatment agent in a carrier isabout 0.5 percent to about 30 percent by weight of the composition.Co-encapsulated with protein or small molecule angiogen treatment agentscould be stabilizers that prolong the biological half-life of thetreatment agent in the carrier upon injection into tissue. Stabilizersmay also be added to impart stability to the treatment agent duringencapsulation. Hydrophilic polymers such as PEG or biomimetic brush-likedextran structures or phosphorylcholine are either coated on the surfaceor the carrier, grafted on the surface of the carrier, blended into thepolymer constituting the carrier, or incorporated into the moleculararchitecture of the polymer constituting the carrier, so the carrier isresistant to phagocytosis upon injection into the target tissuelocation.

E. Catheter Assembly

[0071] One concern of introducing sustained-release treatment agentcompositions into or adjacent blood vessels or the myocardium is thatthe composition remain (at least partially) at the treatment site forthe desired treatment duration (e.g., two to eight weeks). Accordingly,in another embodiment, an apparatus (a catheter assembly) is describedfor accurately locating a treatment agent at a location in a bloodvessel (preferably beyond the media layer) or in a peri-adventitialspace adjacent to a blood vessel, or areas radially outward from aperi-adventitial space, or at tissue location such as the tissue of themyocardium. It is appreciated that a catheter assembly is one techniquefor introducing treatment agents and the following description is notintended to limit the application or placement of the treatment agentcompositions described above.

[0072] Referring now to the drawings, wherein similar parts areidentified by like reference numerals, FIGS. 3,4, and 5 illustrate oneembodiment of a delivery apparatus. In general, the delivery apparatusprovides a system for delivering a substance, such as a treatment agentor a combination of treatment agents optionally presented as a sustainedrelease composition, to or through a desired area of a blood vessel (aphysiological lumen) or tissue in order to treat a localized area of theblood vessel or to treat a localized area of tissue possibly locatedadjacent to the blood vessel. The delivery apparatus is similar incertain respects to the delivery apparatus described in commonly-owned,U.S. patent application Ser. No. 09/746,498 (filed Dec. 21, 2000),titled “Directional Needle Injection Drug Delivery Device”, of Chow, etal., and incorporated herein by reference. The delivery apparatusincludes a catheter assembly 300, which is intended to broadly includeany medical device designed for insertion into a blood vessel orphysiological lumen to permit injection and/or withdrawal of fluids, tomaintain the potency of the lumen, or for any other purpose.

[0073] In one embodiment, catheter assembly 300 is defined by elongatedcatheter body (cannula) 312 having proximal end 313 and distal end 314.FIG. 4 shows catheter assembly 300 through line A-A′ of FIG. 3 (atdistal end 314). FIG. 5 shows catheter assembly 300 through line B-B′ ofFIG. 3 (at proximal end 313).

[0074] Referring to FIG. 3 and FIG. 4, catheter assembly 300 includescatheter body 312 extending from proximal end 313 to distal end 314. Inthis example, guidewire lumen 316 is formed within catheter body 312 forallowing catheter assembly 300 to be fed and maneuvered over guidewire318 (shown at this point within guidewire lumen 316).

[0075] Balloon 320 is incorporated at distal end 314 of catheterassembly 300 and is in fluid communication with inflation lumen 322formed within catheter body 312 of catheter assembly 300. Balloon 320includes balloon wall or membrane 330 which is selectively inflatable todilate from a collapsed configuration to a desired and controlledexpanded configuration. Balloon 320 can be selectively dilated(inflated) by supplying a fluid into inflation lumen 322 at apredetermined rate of pressure through inflation port 323. Balloon wall330 is selectively deflatable, after inflation, to return to thecollapsed configuration or a deflated profile. In one embodiment,balloon wall 330 can be defined by three sections, distal taper wall332, medial working length 334, and proximal taper wall 336. In oneembodiment, proximal taper wall 336 can taper at any suitable angle θ,typically between about 10° to less than about 90°, when balloon 320 isin the expanded configuration.

[0076] Distal taper wall 332, medial working length 334, and proximaltaper wall 336 of balloon wall 330 can be bound together by seams or bemade out of a single seamless material. Balloon 320 can be made from anysuitable material, including, but not limited to, polymers andcopolymers of polyolefins, polyamides, polyesters and the like. Thespecific material employed must be mutually compatible with the fluidsemployed in conjunction with balloon 320 and must be able to stand thepressures that are developed within balloon 320. Balloon wall 330 canhave any suitable thickness so long as the thickness does not compromiseproperties that are critical for achieving optimum performance. Suchproperties include high burst strength, low compliance, goodflexibility, high resistance to fatigue, the ability to fold, theability to cross and re-cross a desired region of treatment or anoccluded region in a lumen, and low susceptibility to defect caused byhandling. By way of example, and not limitation, the thickness can be inthe range of about 10 microns to about 30 microns, the diameter ofballoon 320 in the expanded configuration can be in the range of about 2millimeters (mm) to about 10 mm, and the length can be in the range ofabout 3 mm to about 40 mm, the specific specifications depending on theprocedure for which balloon 320 is to be used and the anatomy and sizeof the target lumen in which balloon 320 is to be inserted.

[0077] Balloon 320 may be dilated (inflated) by the introduction of aliquid into inflation lumen 322. Liquids containing therapeutic and/ordiagnostic agents may also be used to inflate balloon 320. In oneembodiment, balloon 320 may be made of a material that is permeable tosuch therapeutic and/or diagnostic liquids. To inflate balloon 320, thefluid can be supplied into inflation lumen 322 at a predeterminedpressure, for example, between about one and 20 atmospheres.

[0078] Catheter assembly 300 also includes substance delivery assembly338A and substance for injecting a treatment agent into a tissue of aphysiological passageway. In one embodiment, delivery assembly 338Aincludes needle 346A having a lumen with a diameter of, for example,0.004 inches (0.010 cm) to 0.012 inches (0.030 cm). Needle 346A ismovably disposed within delivery lumen 340A formed in catheter body 312.Delivery assembly 338B includes needle 346B movably disposed withindelivery lumen 340B formed in catheter body 312. Delivery lumen 340A anddelivery lumen 340B each extend between distal end 314 and proximal end313. Delivery lumen 340A and delivery lumen 340B can be made from anysuitable material, such as polymers and copolymers of polyamides,polyolefins, polyurethanes, and the like. Access to the proximal end ofdelivery lumen 340A or delivery lumen 340B for insertion of needle 346Aor 346B, respectively is provided through hub 351.

[0079] One or both of delivery lumen 340A and delivery lumen 340B may beused to deliver a treatment agent to a treatment site (e.g., throughneedle 346A and/or needle 346B). Alternatively, one delivery lumen(e.g., delivery lumen 340A via needle 346A) may be used to deliver atreatment agent (e.g., therapeutic angiogenic treatment agent) while theother delivery lumen (e.g., delivery lumen 340B via needle 346B) may beused to deliver a therapeutic substance that is a non-therapeuticangiogenic substance.

[0080] Catheter assembly 300 also includes an imaging assembly. Suitableimaging assemblies include ultrasonic imaging assemblies, opticalimaging assemblies, such as an optical coherence tomography (OCT)assembly, magnetic resonance imaging (MRI). FIGS. 3-5 illustrate anembodiment of a catheter assembly, including an OCT imaging assembly.

[0081] OCT uses short coherence length light (typically with a coherentlength of about 10 to 100 microns) to illuminate the object (e.g., bloodvessel or blood vessel walls). Light reflected from a region of interestwithin the object is combined with a coherent reference beam.Interference occurs between the two beams only when the reference beamand reflective beam have traveled the same distance. FIG. 8 shows onesuitable OCT setup similar in some respects to ones disclosed in U.S.Pat. Nos. 5,465,147; 5,459,570; 5,321,501; 5,291,267; 5,365,325; and5,202,745. A suitable optical assembly for use in conjunction with acatheter assembly is made with fiber optic components that, in oneembodiment, can be passed through the guidewire lumen (e.g., guidewirelumen 316 of FIG. 3). Light having a relatively short coherence length,l_(c) (given by l_(c)=C/Δf, where Δf is the spectral bandwidth) isproduced by light source 380 (e.g., incandescent source, laser source orlight emitting diode of suitable wavelength) and travels through 50/50coupler 382 where it is divided into two paths. One path goes to bloodvessel 383 to be analyzed and the other path goes to a moveablereference mirror 385. The probe beam reflected from sample 383 and thereference beam reflected from reference mirror 385 are combined atcoupler 382 and sent to detector 387. The optical path traversed by thereflected probe beam and the reference beam are matched to within onecoherence length such that coherent interference can occur uponrecombination at coupler 382.

[0082] Phase modulator 384 produces a temporal interference pattern(beats) when recombined with the reference beam. Detector 387 measuresthe amplitude of the beats. The amplitude of the detected interferencesignal is the measure of the amount of light scattered from within acoherence gate interval 388 inside, in this case, blood vessel 383 thatprovides equal path lengths for the probe and reference beams.Interference is produced only for light scattered from blood vessel 383which has traveled the same distance as light reflected from mirror 385.

[0083] In one embodiment, the optical fiber portion of the OCT imagingsystem can be inserted in the guidewire lumen of an over the wirecatheter with guidewire lumen terminating at the imaging wire coupling.The body of the guidewire lumen (e.g., body of lumen 316 of the assemblyof FIG. 3) and the body of the balloon assembly (e.g., body 330 ofballoon assembly in FIG. 3) should be transparent at the distal end toallow optical imaging through the body of the lumen (e.g., through thebody of balloon 320). Thus, once the catheter assembly is placed, at adesired location within, for example, a blood vessel, guidewire 318 maybe removed and replaced with an optical fiber. In a catheter assemblysuch as illustrated in FIG. 3, the replacement of the guidewire with anoptical fiber is done, in one embodiment, at low inflation pressure ofballoon 320.

[0084] Where an optical fiber is substituted for a guidewire, thedimensions of a catheter does not have to be modified. Optical fibershaving an outer diameter of 0.014, 0.018, or 0.032 inches (0.36, 0.46,or 0.81 mm, respectively) are suitable for current guidewire lumens.Other imaging components (e.g., fiber rotator, imaging screen, OCTsystem components, etc.) may be coupled to the optical fiber as itextends out hub 316 at a proximal end of the catheter assembly (e.g., atproximal end 313 of catheter assembly 300). Such components include, butare not limited to, a drive coupling that provides rotation andforward/reverse movement of the optical fiber; a detector, and animaging screen.

[0085]FIG. 9 shows another embodiment of a catheter assembly includingan OCT apparatus. In this embodiment, guidewire 3180 and optical fiber3190 “share” common imaging lumen 3160. Imaging lumen 3160 is preferablymade of a transparent material at the distal end utilized by opticalfiber 3190. Catheter assembly 3000 also includes balloon 3200 withneedle lumens 3400A and 3400B coupled to a proximal portion of balloon3200.

[0086] Referring to FIG. 9, guidewire 3180 exits imaging lumen 3160 atdistal tip 3181 (i.e., distal to balloon 3200). Guidewire 3180 andoptical fiber 3190 are separated in imaging lumen 3160 by plug 3185 of,for example, a polymer or copolymer material, having dimensions suitableto fill the lumen. Suitable polymers include polyimides, polyurethanes,and polyolefins. A portion of plug 3185 may also serve as a ramp forguidewire exit port 3180. In this embodiment, imaging of a blood vessel(e.g., imaging of a wall of a blood vessel for thickness determination)is accomplished from a portion of imaging lumen corresponding with thelocation of balloon 3200. Thus, balloon 3200 is also preferably made ofa transparent material. Flush port 3187 may also be included forclearing imaging portion of imaging lumen 3160.

[0087] At a proximal end, imaging lumen 3160 of FIG. 9 terminates indrive coupling 3195. Drive coupling 3195 provides rotation andforward/reverse direction movement of optical fiber 3190 and connectionto the OCT system.

[0088] In another embodiment, the imaging assembly is based onultrasonic technology. Ultrasonic systems are referenced in U.S. Pat.Nos. 4,794,931; 5,100,185; 5,049,130; 5,485,486; 5,827,313; and5,957,941. In one example, an ultrasonic imaging assembly,representatively including an ultrasonic transducer, may be exchangedfor a guidewire through a guidewire lumen such as described above withreference to the first OCT embodiment. In another embodiment, aguidewire and ultrasonic transducer “share” a common imaging lumensimilar to the embodiment described with reference to FIG. 9 and theaccompanying text. In either example, imaging of, for example, a bloodvessel will take place through the balloon. In the case of ultrasonicimaging, the balloon and guidewire lumen need not be transparent.

[0089]FIGS. 6 and 7 are simplified sectional views of therapeuticsubstance delivery assembly 338A in an undeployed and deployedarrangement, respectively. Delivery lumen 340A includes distal or firstsection 342 and proximal or second section 344. Distal section 342 caninclude overhang section 347 that extends beyond opening 341 to providea means for securing delivery lumen 340A to balloon 320. For example,overhang section 347 can be adhered along the proximal taper wall 336and working length 334 of balloon 320. In this manner, delivery lumen340A is continually supported during, until, and after needle 346A isextended from delivery lumen 340A. In one embodiment, as shown in FIG.7, delivery lumen 340A includes bend region 350 at which distal section342 of delivery lumen 340A is capable of bending (or generally rotating)about pivotal point 351 with respect to proximal section 344. Forexample, to accomplish the pivotal movement, distal section 342 ofdelivery lumen 340A is in contact with proximal taper wall 336 ofballoon 320 (FIG. 3). Accordingly, in response to the inflation ofballoon 320, section 342 moves relative to section 344 to form bendregion 350. In one embodiment, section 342 can move from a substantiallylongitudinal position to a substantially perpendicular position. Thus,the angle θ of bend region 350 can vary between 0° and 90°. In oneexample, after inflation of balloon 320, angle θ can range from betweenabout 10° and 90°, for example, 45°.

[0090] Needle 346A is slidably or movably disposed in delivery lumen340A. Needle 346A includes tissue-piercing tip 352 having dispensingport 353. Dispensing port 353 is in fluid communication with a lumen(not shown) of needle 346A. In one embodiment, the lumen of needle 346Acan be pre-filled with a measured amount of a treatment agent. The lumenof needle 346A connects dispensing port 353 with treatment agentinjection port 359 (FIG. 3), which is configured to be coupled tovarious substance dispensing means of the sort well known in the art,for example, a syringe or fluid pump. Injection port 359 allows ameasured treatment agent to be dispensed from dispensing port 353 asdesired or on command.

[0091] Needle 346A is coupled at proximal end 313 of catheter assembly310 in a needle lock 355 (FIG. 3). Needle lock 355 can be used to secureneedle 346A in position once needle 346A has been either retractedand/or extended from delivery lumen 340A as described below. In oneembodiment, an adjustment knob 357 can be used to set the puncturedistance of needle 346A as it is extended out from delivery lumen 340Aand into the wall of the physiological lumen. For example, adjustmentknob 357 may have calibrations, such that each revolution of theadjustment knob from one calibrated mark to another represents a fixeddistance of travel for needle 346A. The portion of needle 346Aprotruding from delivery lumen 340 can be of any predetermined length,the specific length being dependent upon the desired depth of calibratedpenetration and the procedure for which delivery assembly 338A is to beused. The protruding length of needle 346A can be from about 250 micronsto about four centimeters (cm). It is appreciated that other mechanismsfor securing needle 346A at a retracted or extended position mayalternatively be used, including the incorporation of a mechanical stopoptionally including a signaling (e.g., electrical signaling) device asdescribed in commonly-owned U.S. patent application Ser. No. 09/746,498(filed Dec. 21, 2000), titled “Directional Needle Injection DrugDelivery Device”, and incorporated herein by reference.

[0092] Needle 346A is slidably disposed in delivery lumen 340A, so thatit can move between a first retracted position (FIG. 6) and a secondextended position (FIG. 7). In its first or retracted position,tissue-piercing tip 352 is located inboard of the distal surface ofcatheter body 312, so as to avoid damaging tissue during deployment ofcatheter assembly 310. In its second or extended position,tissue-piercing tip 352 is located outboard of the distal surface ofcatheter body 312, so as to permit needle tip 352 to penetrate thetissue surrounding the physiological passageway in which catheterassembly 310 is disposed.

[0093] Referring again to FIGS. 6 and 7, deflector 360 is disposed alongan inner wall 362 of delivery lumen 340A. In one embodiment, deflector360 includes distal section 370, medial section 372 and proximal section374. In one embodiment, distal section 370 can be supported by deliverylumen 340A by bonding distal section 370 to overhang section 347 ofdelivery lumen 340A. Medial section 372 of deflector 360 can be disposedon inner wall 362 of delivery lumen 340A, such that as delivery lumensection 342 rotates relative to delivery section 344 to form bend region350, deflector 360 is positioned over the outside of the curvature ofbend region 350. Proximal section 374 exits out of delivery lumen 340Aand is adhered to an outside wall 378 of delivery lumen 340A using anadhesive, such as glue or the like.

[0094] Deflector 360 can be any device that will provide a shield toprotect the wall of delivery lumen 340A while being small enough, suchthat deflector 360 does not impact the track of catheter assembly 310 inany significant manner. In one embodiment, deflector 360 can be a ribbonmember. The ribbon member can be made thin, flexible and resilient suchthat the ribbon member can move and bend as delivery lumen sections 342and 344 bend and move relative to each other. Positioning deflector 360of a ribbon member on the outside of the curvature of bend region 350allows deflector 360 to shield the delivery lumen wall from piercing andthe like by needle 346A as needle 346A moves through bend region 350.Deflector 360 also provides a surface upon which needle 346A can be madeto track through bend region 350.

[0095] Deflector 360 is sized to fit into and along inner wall 362 ofdelivery lumen 340A without occluding or interfering with the ability ofneedle 346A to translate through bend region 350. For example, deflector360 can have a thickness of between about 0.0005 inches (0.127 mm) andabout 0.003 inches (0.762 mm). The width of deflector 360 may be betweenabout 0.005 inches (1.27 mm) and about 0.015 inches (3.81 mm). Thelength of deflector 360 may be between about 1 cm and about 10 cm.Deflector 360 can be made from any suitable material, which allowsdeflector 360 to function, such as stainless steel, platinum, aluminumand similar alloy materials with similar material properties. In oneembodiment, deflector 360 can be made from super-elastic alloys, such asnickel titanium alloys, for example NiTi.

[0096] The catheter assembly described with reference to FIG. 3 or FIG.9 may be used to introduce a treatment agent such as described above ata desired location. FIG. 10 illustrates one technique. FIG. 11 presentsa block diagram of one technique. With reference to FIGS. 10 and 11, ina one procedure, guidewire 318 is introduced into, for example, arterialsystem of the patient (e.g., through the femoral artery) until thedistal end of guidewire 318 is upstream of the narrowed lumen of theblood vessel (e.g., upstream of occlusion 185). Catheter assembly 300 ismounted on the proximal end of guidewire 318 and advanced over theguidewire 318 until catheter assembly 300 is position as desired. In theexample shown in FIG. 10, catheter assembly 310 is positioned so thatballoon 320 and delivery lumen 340 a are upstream of the narrowed lumenof LCX 170 (block 410). Angiographic or fluoroscopic techniques may beused to place catheter assembly 300. Once balloon 320 is placed andsubject to low inflation pressure, guidewire 318 is removed and replacedin one embodiment with an optical fiber. In the catheter assembly shownin FIG. 9, the imaging portion of an imaging device (e.g., OCT,ultrasonic, etc.) may be within the imaging lumen as the catheter ispositioned. Once positioned, in this case upstream of occlusion 185, theimaging assembly is utilized to view the blood vessel and identify thevarious layers of the blood vessel (block 420).

[0097] The imaging assembly provides viewable information about thethickness or boundary of the intimal layer 110, media layer 120, andadventitial layer 130 of LCX 170 (See FIG. 1). The imaging assembly mayalso be used to measure a thickness of a portion of the blood vesselwall at the location, e.g., the thickness of the various layers of LCX170.

[0098] LCX 170 is viewed and the layer boundary is identified or athickness of a portion of the blood vessel wall is imaged (and possiblymeasured), (block 140). The treatment site may be identified based onthe imaging (and possibly measuring). In one example, the treatment siteis a peri-adventitial site (e.g., site 190) adjacent to LCX 170. At thispoint, balloon 320 is dilated as shown in FIG. 7 by, for example,delivering a liquid or gas to balloon 320 through inflation lumen 322.The inflation of balloon 320 causes needle lumen 338 to move proximateto or contact the blood vessel wall adjacent to the treatment site.Needle 346A is then advanced a distance into the wall of the bloodvessel (block 140). A real time image may be used to advance needle346A. Alternatively, the advancement may be based on a measurement ofthe blood vessel wall or layer boundary derived from an optical image.

[0099] In the embodiment shown in FIG. 10, needle 346A is advancedthrough the wall of LCX 170 to peri-adventitial site 190. Needle 346A isplaced at a safe distance, determined by the measurement of a thicknessof the blood vessel wall and the proximity of the exit of delivery lumen340A to the blood vessel wall. Adjustment knob 357 may be used toaccurately locate needle tip 346A in the desired peri-adventitialregion. Once in position, a treatment agent, such as a treatment agentis introduced through needle 346A to the treatment site (e.g.,peri-adventitial site 190).

[0100] In the above described embodiment of locating a treatment agentwithin or beyond a blood vessel wall (e.g., at a peri-adventitial site),it is appreciated that an opening is made in or through the bloodvessel. In same instances, it may be desirable to plug or fill theopening following delivery of the treatment agent. This may beaccomplished by introduction through a catheter lumen of cyanoacrylateor similar material that will harden on contact with blood.

[0101] In the above embodiment, an illustration and method was describedto introduce a treatment agent at a peri-adventitial site. It isappreciated that the treatment agent may be introduced to a portion ofthe wall of the blood vessel. In another embodiment, the introduction isat a point beyond the media layer (e.g., beyond media layer 120 inFIG. 1) to the adventitial layer (e.g., adventitial layer 130 in FIG.1). Further, the techniques and treatment agents described may furtherbe used to introduce a treatment agent directly into the tissue of themyocardium.

[0102] In the preceding detailed description, the invention is describedwith reference to specific embodiments thereof. It will, however, beevident that various modifications and changes may be made theretowithout departing from the broader spirit and scope of the invention asset forth in the claims. The specification and drawings are,accordingly, to be regarded in an illustrative rather than a restrictivesense.

What is claimed is:
 1. A method comprising: positioning a deliverydevice at a location in a blood vessel; advancing the delivery device adistance into a wall of the blood vessel to a treatment site beyond anexternal elastic lamina of the blood vessel; and after advancing thedelivery device, introducing a treatment agent through the deliverydevice.
 2. The method of claim 1, further comprising, after positioningthe delivery device, imaging a thickness of a portion of a wall of theblood vessel at the location; and identifying a treatment site based onthe imaging;
 3. The method of claim 2, wherein imaging of a portion of awall of the blood vessel comprises ultrasonic imaging the portion of theblood vessel wall.
 4. The method of claim 2, wherein imaging of aportion of a wall of the blood vessel comprises optical imaging theportion of the vessel wall.
 5. The method of claim 1, wherein thetreatment site comprises a peri-adventitial space.
 6. The method ofclaim 1, wherein the treatment site comprises a site radially outwardfrom a peri-adventitial space.
 7. The method of claim 1, wherein thedelivery device comprises a catheter and positioning the delivery devicecomprises positioning a delivery port for a needle of the catheter at aposition upstream from an obstruction.
 8. The method of claim 1, whereinthe blood vessel is part of a network and another blood vessel in thenetwork other than the blood vessel wherein the catheter is positionedcomprises an obstruction.
 9. The method of claim 1, wherein thetreatment agent is comprised in a sustained release carrier.
 10. Themethod of claim 9, wherein the carrier comprises particles having anaverage diameter on the order of 10 microns or less.
 11. The method ofclaim 10, wherein the carrier includes an opsonin-inhibitor.
 12. Themethod of claim 1, wherein the treatment agent comprises an agent thatinduces an inflammation-inducing response.
 13. The method of claim 12,wherein the treatment agent comprises a thermally conductive material,and the method further comprises, following introducing the treatmentagent, heating the treatment agent.
 14. The method of claim 1, whereinthe treatment agent comprises an agent directed to a specific bindingsite.
 15. A composition comprising: an inflammation-inducing agent,wherein the composition has a particle size suitable for transvasculardelivery.
 16. The composition of claim 15, further comprising a carrierof the inflammation-inducing agent in the form of a particle having aparticle size less than 100 microns.
 17. The composition of claim 16,wherein the carrier comprises a material having a sustained-releaseproperty within a physiological setting.
 18. The composition of claim17, wherein the carrier is selected to sustain the effectiveness of theinflammation-inducing for a period selected from 1 day to 10 weeks. 19.The composition of claim 17, wherein the carrier is selected from thegroup consisting of poly (L-lactide), poly (D,L-lactide), poly(glycolide), poly (lactide-co-glycolide), polycaprolactone,polyanhydride, polydiaxanone, polyorthoester, polyamino acids, poly(trimethylene carbonate), and combinations thereof.
 20. The compositionof claim 15, wherein the inflammation-inducing agent is one of abioresorbable inorganic compound, fibrin, gelatin, chitin, a bacterialpolysaccharide, a metal.
 21. The composition of claim 15, wherein theinflammation-inducing agent is selected from the group consisting of apolycaprolactone, a polyhydroxybutyrate-valerate, a poly(oxy)ethylene, apolyurethane, and a silicone.
 22. The composition of claim 15, furthercomprising an agent directed to specific binding sites.
 23. Acomposition comprising: at least one a treatment agent disposed in acarrier; and an opsonin-inhibitor coupled to the carrier.
 24. Thecomposition of claim 23, wherein the composition is formed as a particlehaving a diameter on the order of up to 10 microns.
 25. The compositionof claim 23, wherein the treatment agent comprises an agent directed tospecific binding sites.
 26. The composition of claim 23, wherein thetreatment agent comprises an inflammation-inducing agent.
 27. Thecomposition of claim 23, wherein the carrier is selected to sustain theeffectiveness of the treatment agent for a period selected from 1 day to10 weeks.
 28. An apparatus comprising: a catheter body capable oftraversing a mammalian blood vessel; a dilatable balloon assemblycoupled to the catheter body comprising a balloon having a proximalwall; at least one needle body disposed within the catheter body andcomprising a lumen having dimensions suitable for a needle to beadvanced therethrough, the at least one needle body comprising an endcoupled to the proximal wall of the balloon; an imaging body disposedwithin the catheter body and comprising a lumen having dimensionssuitable for a portion of an imaging device to be advanced therethroughand adapted to be shared simultaneously or sequentially with aguidewire; and a portion of an imaging device disposed within theimaging body adapted to generate imaging signals of the blood vessel.29. The apparatus of claim 28, wherein the imaging device comprises oneof an optical imaging device and an ultrasonic imaging device.
 30. Theapparatus of claim 28, wherein the imaging body comprises a firsttransparent portion and a second portion with the first portionextending from a proximal end of the catheter body through a portion ofthe balloon, and the first portion is adapted to comprise an imagingdevice and the second portion is adapted to comprise a guidewire. 31.The apparatus of claim 30, wherein the first portion of the imaging bodyis separated from the second portion of the imaging body by a plug.